Combination antiretroviral therapy (ART) consisting of orally-administered small-molecule inhibitors of HIV taken daily has revolutionized the treatment of HIV/AIDS; however, treatment failures continue to occur in a significant fraction of those treated, often due to incomplete patient adherence to the prescribed regimen. Lack of compliance is particularly severe among drug abusers, who consequently are found to have a higher rate of treatment failure. Directly observed treatment (DOT) may support adherence among HIV-positive drug abusers, however the frequency of daily or twice daily ART regimens, potential negative impact on individual freedom, and resource-intensive nature of daily DOT makes this form of support both costly and difficult to sustain. New strategies to treat this population safely and effectively are desperately needed. We propose developing what we believe could be the next revolution in HIV therapy, particularly for drug users: bi-specific or tri-specific antibody-like molecules that could be administered monthly as combination therapy. Antibodies are not only well tolerated and have an excellent safety record, but are also administered infrequently because of their in vivo persistence and long half-life as compared to small molecules. This favorable profile of antibodies has the potential to dramatically increase patient adherence to HIV therapy, leading to decreased treatment failures and better clinical outcomes. Ibalizumab will be used as the backbone of the fusion-antibody constructs because of its well-documented anti-HIV activity and safety record in patients. Re-engineering of ibalizumab will be undertaken to improve on its pharmacokinetics so that low-dose monthly therapy will be readily achievable. Fusion of the recently isolated antibody-like molecules m36 or scFv of PG9 or VRC01 to various parts of ibalizumab will be made and tested empirically, and constructs with superior in vitro profiles will be advanced into efficacy studies in nonhuman primates chronically infected with SHIV. The desired outcome in these nonhuman primate studies is the complete suppression of plasma viral load to non-detectable levels for longer than a year. It is now feasible, for the first time, to think about using mAbs or mAb-like biological molecules to attack HIV at multiple sites simultaneously during its entry process. An ambitious project of this sort is not without risk, but we believe that we have outlined the necessary experiments to minimize these risks as much as possible. In the end, we could only push ahead, realizing that many of the determinants of outcome cannot be determined a priori. It is our expectation that, at the end of this funding period, there will be at least one tri-specific antibody-like molecule or two bi-specific antibody-like molecules that could be advanced into preclinical development as monthly combination antiretroviral therapy.